1. THE T CELL ANTIGEN RECEPTOR
The immune response to foreign antigens is divided into humoral immunity, mediated by B cells, and cellular immunity, mediated by T cells. The receptor molecules used by B cells to recognize antigen are immunoglobulins which recognize conformational epitopes on globular protein. The antigen receptors on T cells are related to immunoglobulins, but recognize processed antigen in association with self MHC molecules (Dembic et al., 1986, Immunol. Today 7:308).
TCR genes, like immunoglobulin genes, consist of regions which rearrange during T cell ontogeny (Chien et al., 1984, Nature 312:31-35; Hedrick et al., 1984, Nature 308:149-153; Yanagi et al., 1984, Nature 308:145-149). The human T cell receptor B chain locus has been extensively studied since the cloning of the first cDNA encoding the .beta.-chain (Yanagi, Y., et al., 1984, Nature 308:145-149; Hedrick et al., 9184, Nature 308:149-152; Siu et al., 1984, Cell 37:393-401). This locus is a gene complex containing variable (V), diversity (D), and joining (J) gene segments which participate in somatic cell rearrangement with a constant (C) region gene segment to encode the .beta. chain of the T cell receptor (Chien et al., 1984, Nature 309:322-326). By in situ hybridization, the TCR.beta. locus resides at 7q35 (Isobe et al., 1985, Science 228:580). By current estimates, this complex spans more than 600 kb and contains 70 to 80 variable region segments (Concannon et al., 1986, Proc. Natl. Acad. Sci. USA 83:6598-6602; Tillinghast et al., 1986, Science 233:879-883; Kimura et al., 1987, Eur. J. Immunol. 17:375-383; Lai et al., 1988, Nature 331:543-546). These V region genes are adjacent to two tandemly organized regions each of which include a D and a C gene segment separated by a cluster of six or seven J region gene segments (Tunnacliffe et al., 1985, Nucleic Acids Res. 13:6651-6661); Toyonaga et al., 1985, Proc. Natl. Acad. Sci. USA 82:8624-8628). Following successful DNA rearrangement of the V, D, and J gene segments, the translated .beta. chain polypeptide pairs with a T cell receptor .alpha. chain and can be expressed on the surface of the T cell (reviewed by Kronenberg et al., 1986, Annu. Rev. Immunol. 4:529-591).
The TCR .alpha. and .delta. locus are next to one another on human chromosome 14. TCR .delta. coding segments are located entirely within the .alpha. gene locus (Satyanarayana et al., 1988, Proc. Natl. Acad. Sci. USA 85:8166-8170; Chien et al., 1987, Nature 330:722-727; Elliott et al., 1988, Nature 331:627-631). It is estimated that there are a minimum of 45-50 V.alpha. regions (Becker et al., Nature 317:430-434) whereas there are only approximately 10 V.delta. regions (Chien et al., 1987, supra). In peripheral blood, two predominant V.delta. genes appear to be expressed, namely, V.delta. 1 and V.delta. 2.
The .gamma. TCR gene was identified, first in mice (Saito et al., 1984, Nature 309:757-762; Kranz et al., 1985, Nature 313:762-755; Hayday et al., 1985, Cell 40:259-269) and then in humans (Lefranc et al., 1985, Nature 316:464-466; Murre et al., 1985, Nature 316:549-552). The human .gamma. TCR locus appears to consist of between five and ten variable, five joining, and two constant region genes (Dialynas et al., 1986, Proc. Natl. Acad. Sci. USA 83:2619).
TCR diversity, and thereby T cell specificity, is derived from several sources (Barth et al., 1985, Nature 316:517-523; Fink et al., 1986, Nature 321:219-225): the multiplicity of germline gene segments (Chien et al., 1984, Nature 309:322-326; Malissen et al., 1984, Cell 37:1101-1110; Gascoigne et al., 1984, Nature 310:387-391; Kavaler et al., 1984, Nature 310:421-423; Siu et al., 1984, Nature 311:344-349; Patten et al., 1984, Nature 312:40-46); combinatorial diversity through the assembly of different V, D, and J segments (Siu et al., 1984, Cell 37:393-401; Goverman et al., 1985, Cell 40:859-867); and junctional flexibility, N-region diversity and the use of either multiple D regions or any of the three translational reading frames for D.beta. segments. TCR diversity does not appear to arise from the somatic hypermutation mechanism observed for immunoglobulins (Barth et al., supra). As a result of these mechanisms, TCRs are generated which differ in their amino-terminal, or N-terminal, domains (constructed from combinations of V, D, and J gene segments) but are similar elsewhere, including their carboxyl-terminal, or C-terminal domains (called constant regions). Accordingly, an extremely large repertoire of TCR is established.
Study of the structure and diversity of the human TCR .beta.-chain variable region genes has led to the grouping of genes into distinct V region subfamilies (Tillinghast et al., 1986, Science 233:879-883; Concannon et al., 1986, Proc. Natl. Acad. Sci. USA 83:6598-6602; Borst et al., 1987, J. Immunol. 139:1952-1959). Each subfamily can be characterized by a consensus sequence and contains similar gene segments exhibiting greater than about 75% similarity in the DNA sequence. For instance, sixteen mouse V.beta. sequences have been categorized into fourteen different subfamilies by a proposed arbitrary but simple numerical nomenclature for the V .beta. gene segments (see Barth et al., 1985, "The Murine T Cell Receptor Employs a Limited Repertoire of Expressed V.beta. Gene Segments" Nature 316:517-523). According to this nomenclature, members of the same subfamily share the first digit and differ in second; therefore the V.beta.8.1, V.beta.8.2 and V.beta.8.3 are all members of the V.beta.8 subfamily. A similar system has been proposed for the human gene segments. In humans, the approximately 60 functional V.beta. genes have been grouped into at least 24 families (Toyonaga and Mak, (1988) Annu. Rev. Immunol. 5:585; Wilson et al., (1988) Immunol. Rev. 101:149; and Robinson, M. A. (1991) J. Immunol. 146:4392).